Defining a Dystonia Specific Spiking Signature in Cerebellar Nuclei Cells

定义小脑核细胞中肌张力障碍特异性尖峰特征

• 批准号: 10577322
• 负责人: Meike Esther Van Der Heijden
• 金额: $ 12.18万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-15 至 2023-12-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10577322
• 关键词: Acute; Adult; Affect; Age; Animal Model; Ataxia; Award; Basal Ganglia; Behavior; Biological Markers; Body part; Brain Stem; Cell Nucleus; Cell physiology; Cerebellar Diseases; Cerebellar Nuclei; Cerebellum; Child; Childhood Onset Dystonias; Clinical; Databases; Deep Brain Stimulation; Defect; Development; Disease; Disease susceptibility; Dystonia; Early Onset Dystonia; Electrophysiology (science); Etiology; Fiber; Foundations; Functional disorder; Funding; Genetic; Genetic Heterogeneity; Goals; Heart; Hereditary Dystonia; Human; Impairment; Knowledge; Laboratories; Leadership; Medical center; Medicine; Mentors; Mentorship; Modeling; Motion; Motor; Motor Cortex; Movement; Movement Disorders; Mus; Muscle; Muscle Contraction; Neuroanatomy; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurologic; Neurologic Deficit; Neurons; Neurosciences; Neurosciences Research; Output; Pain; Paper; Pathway interactions; Patients; Pattern; Pediatric Hospitals; Persons; Phenotype; Posture; Primary Dystonias; Purkinje Cells; Research; Research Institute; Role; Scientist; Severities; Signal Transduction; Smooth Muscle; Source; Symptoms; Testing; Texas; Thalamic structure; Training; Tremor; United States; United States National Institutes of Health; Work; career; career development; college; computational platform; design; effective therapy; experimental study; in vivo; insight; motor control; motor deficit; motor disorder; motor impairment; mouse genetics; mouse model; mutant; mutation carrier; nervous system disorder; neural network classifier; neuron development; neurophysiology; neurotransmission; optogenetics; pharmacologic; postnatal; prevent; programs; pup; respiratory; skills; stem; therapeutic target; timeline

Project summary and significance: Dystonia is characterized by involuntary muscle contractions and is estimated to be the third most common movement disorder in the United States. Dystonia can be the primary symptom in patients of all ages or present as a secondary symptom in patients with neurodevelopmental and neurodegenerative disorders and affects function of many nodes in the motor circuit, including the thalamus, basal ganglia, motor cortex, and cerebellum. This neurological diversity – in addition to the genetic heterogeneity of hereditary dystonia – has made it difficult to pinpoint therapeutic targets. A better understanding of the pathophysiology of dystonia is indispensable to the development of more effective treatments. Recent studies suggest that cerebellar pathophysiology forms a shared mechanism for the inception of etiologically distinct dystonias; nearly all animal models with overt dystonia-like symptoms have abnormalities in the spiking activity of cerebellar neurons. Yet, the precise mechanism of cerebellar dysfunction in dystonia is enigmatic, especially because cerebellar pathophysiology is primarily known to cause other motor disorders, like ataxia and tremor. This Pathway to Independence Award proposal leverages quantitative, in vivo electrophysiology in genetic, developmental, and optogenetic mouse models of dystonia to define a dystonia-specific spiking signature in cerebellar output neurons, and to deduce the developmental divergence of cerebellar function between healthy and dystonic mice. This knowledge will provide a biomarker and therapeutic target for dystonia, which will be invaluable for designing new treatments that alleviate or prevent symptoms onset in patients or mutation carriers. Candidate and career development: Dr. Meike van der Heijden was trained in developmental neuroscience in the laboratory of Dr. Huda Zoghbi, where she used intersectional genetics to unveil the function and identity of brainstem respiratory neurons essential for postnatal survival. She then joined the laboratory of Dr. Roy Sillitoe, a world-leader in cerebellar neuroscience with a strong record of NIH funding, mentorship, and scientific leadership. Here, she developed an analytical platform and generated a database to assess spiking activity in cerebellar neurons across mouse models of cerebellar disease (dystonia, ataxia, tremor), and studied how impaired maturation of cerebellar Purkinje cell function leads to neurological deficits. In this proposal, Dr. Van der Heijden will build on her skills in in vivo electrophysiology, mouse genetics, and neuroanatomy and expand her analytical tool-kit, broaden her skills in unbiased quantitative motor function assessment, and acquire proficiency in acute manipulation of cerebellar circuits using optogenetics. All experiments will be conducted in the Neurological Research Institute, a collaborative research institute for clinical excellence and world-class neuroscience research built by Texas Children’s Hospital and Baylor College of Medicine in the heart of the Texas Medical Center. The professional training plan is designed to launch Dr. Van der Heijden’s career as a successful scientist focused on the understanding of cerebellar development in the pathophysiology of dystonia.

项目概述及意义：肌张力障碍是以不自主肌肉收缩为特征， 估计是美国第三常见的运动障碍。肌张力障碍可能是 所有年龄段患者的症状或在神经发育和 神经退行性疾病并影响运动回路中许多节点的功能，包括丘脑， 基底神经节、运动皮质和小脑。这种神经多样性-除了遗传异质性 遗传性肌张力障碍-使得很难确定治疗目标。更好地理解 肌张力障碍的病理生理学对于开发更有效的治疗是不可缺少的。最近的研究 表明小脑病理生理学形成了一种共同的机制， 肌张力障碍;几乎所有具有明显肌张力障碍样症状的动物模型的峰值活动都异常 小脑神经元。然而，在肌张力障碍中小脑功能障碍的确切机制是谜，特别是 因为小脑的病理生理学主要是已知引起其他运动障碍，如共济失调和震颤。 这个独立之路奖提案利用了遗传学中的定量体内电生理学， 发育和光遗传学的肌张力障碍小鼠模型，以定义肌张力障碍特异性尖峰信号， 小脑输出神经元，并推断小脑功能的发育分歧之间的健康 和肌张力障碍小鼠。这一知识将为肌张力障碍提供生物标志物和治疗靶点，这将是 对于设计新的治疗方法，减轻或预防患者或突变携带者的症状发作是非常宝贵的。 候选人和职业发展：Meike货车der Heijden博士在1999年接受了发育神经科学的培训。 Huda Zoghbi博士的实验室，在那里她使用交叉遗传学来揭示 脑干呼吸神经元对出生后的生存至关重要。然后她加入了罗伊·西利托博士的实验室， 小脑神经科学的世界领导者，拥有NIH资助，指导和科学研究的良好记录 领导在这里，她开发了一个分析平台，并生成了一个数据库，以评估 小脑疾病（肌张力障碍，共济失调，震颤）小鼠模型的小脑神经元，并研究了如何 小脑浦肯野细胞功能成熟受损导致神经功能缺陷。在这份提案中，货车博士 der Heijden将利用她在体内电生理学，小鼠遗传学和神经解剖学方面的技能， 她的分析工具包，扩大了她的技能，在公正的定量运动功能评估，并获得 熟练使用光遗传学对小脑回路进行急性操作。所有实验将在 神经学研究所，一个临床卓越和世界一流的合作研究所 由德克萨斯儿童医院和贝勒医学院建立的神经科学研究， 德州医疗中心专业培训计划旨在启动货车德海登博士的职业生涯， 一位成功的科学家专注于理解小脑发育在肌张力障碍的病理生理学中的作用。